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Ethyl PAK modified biscarboline piperazine diketone and preparation, activity and application thereof

A technology of diketone and ethyl, applied in the direction of medical preparations containing active ingredients, chemical instruments and methods, tripeptide components, etc., can solve problems such as no curative effect, chest cavity and abdominal cavity bleeding

Active Publication Date: 2020-12-01
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are two insurmountable problems in the treatment of ischemic stroke with rtPA
The first complication is that rtPA is not effective in patients with ischemic stroke >4 hours
The second problem is that continuous use of rtPA can cause cerebral, thoracic and abdominal hemorrhage

Method used

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  • Ethyl PAK modified biscarboline piperazine diketone and preparation, activity and application thereof
  • Ethyl PAK modified biscarboline piperazine diketone and preparation, activity and application thereof
  • Ethyl PAK modified biscarboline piperazine diketone and preparation, activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl ester (1)

[0021] Add 5 mL of 1,1,3,3-tetramethoxypropane and 3.5 mL of trifluoroacetic acid to 150 mL of dichloromethane under stirring at 0°C, react for 40 minutes, then add 5 g (17.00 mmol) of Trp-OBzl, The reaction was carried out at 40°C. After reacting for 4 hours, the pH value of the reaction solution was adjusted to 7 with concentrated ammonia water at 0°C with stirring, concentrated under reduced pressure, and the residue was dissolved in 100 mL of dichloromethane, washed three times with saturated aqueous sodium bicarbonate solution, saturated chlorinated The sodium solution was washed 3 times, the dichloromethane phase was dried with anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow oil, which was purified by silica gel column chromatography to obtain 5.50 g (82%)...

Embodiment 2

[0022] Example 2 Preparation of (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid (2)

[0023] 5.50g (13.96mmol) (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl The ester (1) was dissolved in 50 mL of acetone, and NaOH aqueous solution (2M) was added thereto under stirring at 0° C. to adjust the pH value of the solution to 12, and reacted for 3 hours to keep the pH value of the reaction solution at 12. Thereafter, the pH was adjusted to neutral with saturated potassium hydrogensulfate aqueous solution, and concentrated under reduced pressure. 50 mL of acetone was added to the residue, the insoluble solid was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain 3.63 g (86%) of the title compound as a yellow sticky substance. ESI-MS(m / e):303[M-H] - .

Embodiment 3

[0024] Example 3 Preparation of (2'S,5'S)-tetrahydropyrazine[1',2':1,6]bis[1S,1R-(1-dimethoxyeth-1-yl)-2,3,4 ,9-Tetrahydro-1H-pyridino[3,4-b]indole]-1',4'-dione (3)

[0025] 3.63g (11.94mmol) (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid (2 ) was dissolved in 20 mL of anhydrous N,N-dimethylformamide, and then 5.44 g (14.32 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate, the solution was adjusted to pH 8 with N-methylmorpholine under stirring at 0°C, and after stirring at room temperature for 16 hours, 150 mL of distilled water was added to the reaction solution, followed by extraction with dichloromethane ( 50mL×3), combined the dichloromethane phase, and then washed with saturated aqueous sodium chloride solution (50mL×3), the dichloromethane phase was dried with anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow The oil was ...

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Abstract

The invention discloses (2'S,5'S)-tetrahydropyrazine[1',2':1,6]bis[1S,1R-(1-ethyl-Pro-Ala-Lys)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole]-1',4'-diketone as shown in a formula in the specification, apreparation method of the compound, the thrombolytic activity of the compound, the antithrombotic activity of the compound, and the characteristic that the compound is still effective for ischemic stroke attacking for 24 hours. Therefore, the invention discloses an application of the compound in the preparation of thrombolytic drugs, an application of the compound in the preparation of antithrombotic drugs, an application of the compound in the preparation of drugs which are still effective for ischemic stroke attacking for 24 hours, and an application of the compound in the preparation of drugs which have triple effects of dissolving thrombus, resisting thrombus and being still effective for ischemic stroke attacking for 24 hours.

Description

technical field [0001] The present invention relates to (2'S,5'S)-tetrahydropyrazine[1',2':1,6]bis[1S,1R-(1-ethyl-Pro-Ala-Lys)-2,3,4, 9-tetrahydro-1H-pyridine[3,4-b]indole]-1',4'-dione, related to its preparation method, related to its thrombolytic activity, related to its antithrombotic activity and related to It remains effective for 24 hours after the onset of ischemic stroke. Therefore the present invention relates to its application in the preparation of thrombolytic drugs, to its application in the preparation of antithrombotic drugs, to its application in the preparation of drugs that are still effective for 24 hours after the onset of ischemic stroke, and to its use in the preparation of drugs with lytic properties. Thrombotic, antithrombotic, and triple-action drugs that are effective for 24 hours after the onset of ischemic stroke. The invention belongs to the field of biomedicine. [0002] technical background [0003] Ischemic stroke is a common and serious cer...

Claims

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Application Information

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IPC IPC(8): C07K5/097A61K38/06A61P7/02A61P9/10
CPCC07K5/0823C07K19/00A61P7/02A61P9/10A61K38/00
Inventor 赵明彭师奇冯琦琦张娟凤
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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